Project Summary Development of novel cancer therapies that selectively target cancer cells through mechanisms unique to cancer biology remains an important challenge in the fight against cancer. This task is made even more difficult due to the vast number of different cancer types, each with its own unique biology. However, certain biological pathways are common to many different varieties of cancer, providing an opportunity for the development of a general therapy for cancer treatment. One such pathway is hypoxia-induced angiogenesis, which has been suggested to be the driving force for around 70% of human cancer types. Development of a selective small molecule inhibitor of this pathway would represent a major step forward in cancer treatment, enabling effective treatment of a diverse range of different cancer types. Pleurotin is an antibiotic fungal metabolite first isolated in 1947 and found to possess powerful anticancer properties. Despite being known for 70 years, the exact mechanism of pleurotin?s anticancer effect remains unknown, although it is proposed to function through inhibition of hypoxia-induced angiogenesis. This proposed biological mode of action has made pleurotin a high value target for both biological studies and chemical synthesis. This research proposal describes a short chemical synthesis of pleurotin through rapid formation of the challenging trans- hydrindane motif found in the natural product. Due to the prevalence of trans-hydrindane structures in a variety of natural products, this strategy should enable the synthesis of a wealth of molecules with varied biological activity. The research plan also outlines the synthesis and biological testing of novel pleurotin analogs. The combination of analog synthesis and biological assays will allow for the elucidation of the mechanism of pleurotin?s anticancer properties, potentially leading to new general treatments for cancer. Overall, the proposed research will allow for the rapid synthesis of an important natural product and provide valuable information on the mechanism of inhibition of a prevalent driving force in human cancer.